Background: The coronavirus disease 2019 (COVID-19) pandemic has affected billions of lives worldwide. Nepal, like many other countries, was severely affected by the pandemic. The socio-economic and health conditions of key populations, such as pregnant and lactating women, people with disabilities and morbidities were at high risk. In 2021, Adventist Development Relief Agency (ADRA) Nepal in collaboration with the Government of Nepal conducted a vaccine hesitancy survey in seven provinces of Nepal. The results revealed a high vaccine hesitancy in Madhesh province (37.5%), which was mostly attributable to the difficulties in accessing the vaccination service (26%). Methods: To eliminate the barriers identified during vaccine hesitancy survey, Mobile COVID-19 Vaccination Service (MoCoVs) was started in coordination with the government to provide door-to-door vaccination service to pregnant and lactating women, people with disabilities and morbidities. A dedicated vaccination vehicle with a team of vaccinator and a nurse equipped with Adverse Effect Following Immunization kits, vaccine storage boxes, syringe disposal boxes were deployed to seven districts with low vaccination coverage in the province. Results: MoCoVs was able to reach high-risk beneficiaries (elderlies-11%, people with disabilities and morbidities-9%), the majority of whom were female (57%), including 10% of pregnant and lactating women. The vaccination coverage increased from 24% to 72%, with the MoCoVs being responsible for the enhanced immunisation reach to high-risk populations. Conclusions: The MoCoVs approach was highly effective in reaching the marginalized population, who generally lacked access to vaccination services. The door-to-door vaccination service was highly effective and easily replicable during public health emergencies.